tbuckley/cabot-search huggingface dataset:
Abstract 3532: Activator protein-1 (AP-1) signaling inhibits the growth of Ewing sarcoma cells in response to DNA replication stress
Authors: David Gordon, Emma Croushore, Stacia Koppenhafer, Kelli Goss, Elizabeth Geary
Journal: Cancer Research (2023)

Abstract Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis of deoxyribonucleoside triphosphates (dNTPs) and is required for DNA replication and the repair of DNA damage. Multiple types of cancer, including Ewing sarcoma tumors, are sensitive to RNR inhibitors or a reduction in the levels of either the RRM1 or RRM2 subunits of RNR. However, the polypharmacology and off-target effects of RNR inhibitors has complicated the identification of the precise mechanisms that regulate sensitivity and resistance to this class of drugs. Consequently, we used a conditional knockout (CRISPR/Cas9) and rescue approach to target RRM1 in Ewing sarcoma cells and identified that loss of RRM1 results in upregulation of the expression of multiple members of the activator protein-1 (AP-1) transcription factor complex, including c-Jun and c-Fos. This upregulation of AP-1 is mediated, in part, by SLFN11, which is expressed at high levels in Ewing sarcoma tumor and other pediatric sarcomas. Notably, the inducible expression of c-Jun and c-Fos in Ewing sarcoma cells impairs cell growth, downregulates the expression of the stem cell factor Sox2, and upregulates markers of cellular differentiation. In addition, small-molecule inhibitors of RNR, including gemcitabine and hydroxyurea, and HDAC inhibitors, which reduce the level of the RRM1 protein, also activate this AP-1 signaling pathway in Ewing sarcoma cells. Overall, these results provide novel insight into the critical pathways activated by loss of RNR activity and the mechanisms of action of inhibitors of RNR. Citation Format: David Gordon, Emma Croushore, Stacia Koppenhafer, Kelli Goss, Elizabeth Geary. Activator protein-1 (AP-1) signaling inhibits the growth of Ewing sarcoma cells in response to DNA replication stress. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3532.
Abstract 280: Targeting mRNA pseudouridylation to suppress neuroblastoma metabolism
Authors: Anamika Gupta, Mohit Bansal, Han-Fei Ding
Journal: Cancer Research (2023)

Abstract Pseudouridylation of mRNA is a common epigenetic modification that reduces RNA conformational flexibility and increases its structural stability and may increase its availability for translation. RNA pseudouridylation is catalyzed by the family of pseudouridine synthases, including dyskerin pseudouridine synthase 1 (DKC1). Here we report the DKC1 gene is a direct transcriptional target of MYCN, which is a major oncogene in driving the development of high-risk neuroblastoma, a childhood cancer with a poor prognosis. The transcriptional upregulation of DKC1 expression in MYCN-amplified cells is of functional significance, as DKC1 depletion by RNA interference inhibits the proliferation of neuroblastoma cell lines. Furthermore, gene expression profiling reveals that DKC1 has a key role in the regulation of amino acid biosynthesis enzymes. Genetic and pharmacological inhibition of DKC1 reduces the expression of ATF4 and its downstream target genes involved in amino acid synthesis and transport. These findings reveal a critical role of DKC1 in sustaining the proliferation of neuroblastoma cells by promoting amino acid metabolism, which could be exploited as a therapeutic strategy against high-risk neuroblastoma. Citation Format: Anamika Gupta, Mohit Bansal, Han-Fei Ding. Targeting mRNA pseudouridylation to suppress neuroblastoma metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 280.
Abstract 4701: Spatial resolution of tumor and immune cell lineages in the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC)
Authors: Lisa Arvidson, Reginaldo Prioli, Samuel Jensen, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Melinda L. Angus-Hill
Journal: Cancer Research (2023)

Abstract Understanding how the tumor microenvironment (TME) evolves during tumorigenesis and therapeutic response is crucial to developing personalized treatments with the goal of improving cancer therapy. With robust and comprehensive multiplexed imaging technologies, immune biomarker antibodies can be used to interrogate immune cell lineages and structures. When combined with specific oncology biomarker antibodies, this approach can capture the immune response within the TME in a variety of neoplasms. The Cell DIVETM Multiplex Imaging Solution allows probing and imaging of dozens of biomarkers on a whole single tissue section using an iterative staining and dye inactivation workflow. The broad portfolio of robust IHC-validated antibodies from Cell Signaling Technology (CST) enables the detection of key proteins in the TME, allowing immune cell detection and phenotyping in tissue. Here, we demonstrate multiplexed Cell DIVE imaging using a novel CST panel to probe pancreatic ductal adenocarcinoma (PDAC). These biomarker antibodies define the immune cell landscape in the hypoxic tumor. Development of the antibody panel required minimal optimization, enabled the identification of complex cell types and revealed their cell-to-cell interactions within the tumor microenvironment. The availability of cell type specific biomarkers, combined with the ability to interrogate using multiplexed tissue imaging, provides unprecedented and novel insights and spatial resolution of immune cell populations with many cell types in the TME. Citation Format: Lisa Arvidson, Reginaldo Prioli, Samuel Jensen, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Melinda L. Angus-Hill. Spatial resolution of tumor and immune cell lineages in the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4701.
Abstract 6527: Fusion genes as novel putative biomarkers for head and neck squamous cell carcinomas
Authors: Yabdiel A. Ramos Valerio, Hannah C. Van Wyk, Esther Peterson Peguero, Josué Pérez Santiago
Journal: Cancer Research (2023)

Abstract Head and neck squamous cell carcinomas (HNSCC) are highly aggressive types of cancers with a complex molecular etiology of disease and consequently result in delayed clinical detection, poor prognosis, and limited treatment strategies. Fusion genes, a hallmark of cancer, may be targeted for early identification and treatment of HNSCC; however, studies characterizing fusion genes in HNSCC remain limited. Oral Human Papillomavirus (HPV) infection is a major cause of HNSCC and can also promote the acquisition of fusion genes due to the genomic instability induced by its integration. Here, we retrieved RNA-sequencing data from 36 HNSCC tumors (18 HPV+ and 18 HPV-, GEO Accession: GSE74956) to identify fusion genes using the STAR fusion algorithm in each sample. Statistical analyses were performed in R statistical software. A total of 10 fusion genes were identified in at least 4 of the samples regardless of HPV status. We identified 3 fusion genes that were present in at least 4 of the HPV+ tumors: PMS2P9-CCDC146, MACC1-AC005062.1, AC096711.2-RPL7AP28, and one solely present in HPV- tumors: CTSC-RAB38. The remaining 6 fusion genes were present in both HPV+ and HPV- tumors: TVP23C-CDRT4, AC009271.1-LINC01905, MIR205HG-AOPEP, SEPTIN7P2-PSPH, KRT5-KRT84, KANSL1-ARL17A. While 4 of the identified fusion genes had been previously associated with cancer, there were 6 novel identified fusion genes, in which one or both partner genes have been associated with different cancers. Additionally, the identified fusion genes may be a product of transcription read-through of neighbor genes. The fusion genes associated with HPV infection might explain biological disparities in HPV+ versus HPV- HNSCC and may be targets for the prevention and diagnosis of HNSCC. Future studies need to determine the functional impact of the identified fusion genes in HPV+ tumors. Citation Format: Yabdiel A. Ramos Valerio, Hannah C. Van Wyk, Esther Peterson Peguero, Josué Pérez Santiago. Fusion genes as novel putative biomarkers for head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6527.
Abstract 504: BPI-472372: a potent and orally bioavailable small molecule inhibitor of CD73 for cancer immunotherapy
Authors: Han Han, Xiaofeng Yang, Ying Zhao, Jin Wang, Xiang Yang, Xuepeng Ju, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Jing Guo, Cheng Yang, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang
Journal: Cancer Research (2023)

Abstract CD73, also known as ecto-5'-nucleotidase, plays a major role in converting extracellular adenosine monophosphate (AMP) to immunosuppressive adenosine. It is frequently overexpressed across a variety of cancers. High adenosine level in the tumor microenvironment, predominantly signaling through the A2a/A2b receptors, suppresses innate and adaptive immune responses and mediates tumor immune evasion. CD73 overexpression is correlated with poor prognosis in several tumor types. Inhibition of CD73 to reduce adenosine production is a promising therapeutic approach for the treatment of cancer. Both monoclonal antibodies and small molecule inhibitors are being explored to target CD73. Small molecule CD73 inhibitor with good balance of activity and ADME properties are rare. Here we present BPI-472372, a potent, selective, and orally bioavailable small molecule CD73 inhibitor. It strongly inhibits both soluble and cell-bound CD73, with no off-target activity on other related nucleotidases (NTPDases 1/2/3/5), nor on a large panel of enzymes, receptors, and ion channels. BPI-472372 reversed AMP-induced CD4+ T cell suppression in a dose-dependent manner. In vivo, BPI-472372 exhibited anti-tumor effect in MC38 syngeneic mouse model with no visible adverse effect. Moreover, enhanced tumor growth inhibition activity was observed when BPI-472372 was combined with durvalumab (anti-PD-L1) in humanized PD-L1 syngeneic MC38 model. BPI-472372 exhibited desirable drug-like properties including high permeability, low hepatocytes clearance, and adequate oral exposure across multiple pre-clinical species. GLP toxicity study indicated that BPI-472372 was well tolerated at high dose following 4 weeks repeated administration in both mouse and dog. Taken together, BPI-472372 is a potent and orally bioavailable small molecule CD73 inhibitor with single agent anti-tumor efficacy, favorable ADME properties, and a wide therapeutic index. Citation Format: Han Han, Xiaofeng Yang, Ying Zhao, Jin Wang, Xiang Yang, Xuepeng Ju, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Jing Guo, Cheng Yang, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-472372: a potent and orally bioavailable small molecule inhibitor of CD73 for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 504.
Abstract 4695: Expansion of the extracellular proximity labeling (ePL) technique to novel matrisome targets
Authors: Joshua Rich, Sadeechya Gurung, Sukhbir Kaur, David Roberts, William Stetler-Stevenson, David Peeney
Journal: Cancer Research (2023)

Abstract The extracellular matrix (ECM) is a complex and dynamic meshwork of extracellular macromolecules that plays a key role in cancer progression and metastasis. The matrisome encompasses the genes encoding ECM and ECM-associated secretory proteins, and elucidating the protein-protein interactions (PPIs) of the matrisome is a promising area of study in the quest for a better understanding of cancer pathology and therapeutics. Proximity labeling, a powerful technique for investigating protein interactomes based on enzyme-fusion constructs and affinity chromatography, has considerable potential in detailing the protein-protein interactions of the matrisome. We have recently had success in developing a proximity labeling approach based on fusion constructs containing the biotinylating enzymes BioID2 and TurboID. We apply this approach to gain new insights into the interactome of the matrisome protein tissue inhibitor of metalloproteinase 2 (TIMP2), a protein found to have antitumorigenic potential. At present, we seek to expand this approach to other ECM protein targets, including tissue inhibitor of metalloproteinase 3 (TIMP3) and thrombospondin-1 (THBS-1). TIMP3 has been shown to possess anti-tumor properties, with loss of TIMP3 function associated with poor prognosis in multiple cancers. THBS-1 is a large (129 kDa) ECM protein that is relatively promiscuous with diverse functions in the tumor microenvironment. Expression of THBS-1 is frequently lost during oncogenesis, and such loss is associated with poor prognosis in some cancers. We describe how ePL can be expanded to these matrisome targets in different cellular systems (adherent vs. suspension) and show that ePL assays can be performed with stable and transient transgene expression. We show that ePL is a suitable method for studying PPIs in novel matrisome targets and expect to apply the technique to further targets in the near future. Citation Format: Joshua Rich, Sadeechya Gurung, Sukhbir Kaur, David Roberts, William Stetler-Stevenson, David Peeney. Expansion of the extracellular proximity labeling (ePL) technique to novel matrisome targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4695.
Abstract 490: Discovery of novel, potent and orally available MAT2A inhibitors
Authors: Xuxing Chen, Jing Li, Yanhong Chen
Journal: Cancer Research (2023)

Abstract The methylthioadenosine phosphorylase (MTAP) gene is co-deleted with CDKN2A in approximately 15% of all cancers, but targeting a loss of function mutant is not trivial due to the lack of a target protein. The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We describe here potent and orally bioavailable MAT2A inhibitors (“Euregen MAT2Ais”) with superior potency and selectivity compared to AG-270. Euregen MAT2Ais bind at the interface of two MAT2A subunits and exhibit low nanomolar IC50s in biochemical assay. These compounds demonstrated more than 20-fold selective for MTAP−/− cell lines over isogenic MTAP WT. Oral administration of Euregen MAT2Ais drived dose-dependent antitumor activity without meaningful body weight loss in HCT116 MTAP−/− xenograft model. Furthermore, Euregen MAT2Ais revealed excellent oral bioavailability and PK properties in pre-clinical species. We are optimizing multiple MAT2A inhibitors that exhibit activity across a wide range of cancers with MTAP-deletion. Citation Format: Xuxing Chen, Jing Li, Yanhong Chen. Discovery of novel, potent and orally available MAT2A inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 490.
Abstract 2237: Inhibition of HSF1 demonstrates therapeutic efficacy in preclinical models of cholangiocarcinoma
Authors: Danielle M. Carlson, Amro Abdelrahman, Alessandro Fogliati, Isaac Lynch, Jennifer Tomlinson, Mark Truty, Rory Smoot
Journal: Cancer Research (2023)

Abstract Introduction: Cholangiocarcinoma (CCA) is a highly lethal, and biologically heterogenous malignancy arising from the biliary tree. With only moderate responses to cytotoxic chemotherapy and despite the development of targeted therapies, treatment success has been hindered by primary or acquired resistance. New therapeutic strategies are necessary to improve outcomes in these patients. NXP800 is a heat shock factor 1 (HSF1) small-molecule inhibitor with activity previously noted in ovarian cancers with ARID1A mutations. ARID1A mutations are common, well-known players in cholangiocarcinoma. In preclinical exploratory studies, we examined treatment responses in validated cholangiocarcinoma patient derived xenograft (PDX) models. Methods: In our preliminary studies we evaluated response to HSF1 inhibition in a single, ARID1A wildtype PDX model. Xenografts were expanded into the flank of NOD/SCID mice and treatment begun when tumors averaged 120mm3. 16 tumor bearing mice were randomized and 8 mice were grouped into both the treatment and control arms. Mice were then treated with either NXP800 (35 mg/kg), in the treatment arm, or vehicle, in the control arm, via oral gavage 5 days on, 2 days off, for 28 days. Tumor volume and animal weight were collected twice weekly. Results: After screening of our Human CCA PDX library of 57 patients, we identified an established and histologically validated PDX from a patient with intrahepatic cholangiocarcinoma obtained at surgical resection. Molecular characterization of the tumor identified NRAS Q61 mutation, FGFR1 and FGFR2 overexpression, androgen receptor overexpression, microsatellite stability, and a total tumor mutational burden of 2.6. RNA sequencing was completed and an evaluation of a 21-gene signature of YAP activity had identified this PDX as having an elevated activity signature compared to a cohort of 27 additional PDX tumors. Treatment with NXP800 was associated with a statistically significant decrease in tumor size compared to control tumor bearing mice, with a mean difference of the delta in tumor volume (852.6 mm3; 95% CI: 321 - 1384; P-value = 0.0057). Conclusion: NXP800, a HSF1 inhibitor, demonstrated significant therapeutic activity in a cholangiocarcinoma PDX. Further studies are needed and being performed to determine the role of HSF1 inhibition in human cholangiocarcinoma. Citation Format: Danielle M. Carlson, Amro Abdelrahman, Alessandro Fogliati, Isaac Lynch, Jennifer Tomlinson, Mark Truty, Rory Smoot. Inhibition of HSF1 demonstrates therapeutic efficacy in preclinical models of cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2237.
Abstract 3063: A novel mechanism for therapeutic targeting of the glucocorticoid receptor in triple negative breast cancer
Authors: Shagufta H. Khan, Christian Carbe, Jun Ling, Raj Kumar
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) is frequently diagnosed in younger women and is prevalent in African American women. Most TNBCs are highly aggressive with early pattern of metastasis, and with limited treatment options and poor prognosis. Finding effective therapeutic targets for TNBC has proven difficult so far. Therefore, there is an urgent need to develop new and novel therapeutic management of these patients. Recent studies have shown that glucocorticoid receptor (GR) is a mediator of pro-survival genes in TNBC cells, and its expression is predictive of increased risk of metastasis in TNBC tumors and decreased rate of patient survival. Therefore, blocking the effects of GR should be beneficial for TNBC patients. However, GR antagonists such as RU486 (mifepristone) targeting AF2/coactivators have shown only partial success in TNBC cell lines as well as in animal models. Based on our previous data we hypothesize that since in TNBC cells, the GR is constitutively active; therefore, attempts to block/inhibit GR activity through classic antagonists such as mifepristone that bind to ligand binding pocket of the receptor will have a limited clinical efficacy and higher side effects. To circumvent this problem, in this study, we propose a novel and innovative therapeutic approach to target constitutively active AF1 domain of the GR, which exists in an intrinsically disordered (ID) conformation. In this study, we tested our hypothesis that inhibiting/blocking TATA-box binding protein (TBP)-mediated GR’s AF1 activity by our newly identified molecule, PepT will attenuate TNBC cell survival via altering associated endogenous gene expressions. Our binding kinetics of AF1 showed that PepT binds to AF1 with about 10-fold higher affinity when compared with TBP’s binding to AF1. AF1 pre-bound with PepT fails to bind to TBP suggesting that PepT competes and blocks AF1-TBP interaction. We also found that treatment of MDA-MB-231 cells with PepT results in significant attenuation of cell viability and proliferation. Together, these results support our hypothesis that PepT has potential to kill TNBC cells by blocking GR AF1:co-regulator interactions. Citation Format: Shagufta H. Khan, Christian Carbe, Jun Ling, Raj Kumar. A novel mechanism for therapeutic targeting of the glucocorticoid receptor in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3063.